Glioma is the general name of tumors originating from ependymoblasts, which is the stem cell for glia, in the course of the differentiation thereof into ependymal cell, astroglia and oligodendroglia [Seikagaku Jiten (Dictionary of Biochemistry), the third edition, Tokyo Kagaku Dojin, Tokyo, 1998].
Glioblastoms multiforme (referred to as glioblastoma hereinafter) highly invades the central nervous system and is ranked at a higher malignancy level among gliomas. Thus, glioblastoma is a typical one of malignant brain tumors.
Additionally, the lethal rate thereof is very high so that the onset thereof induces death in 9 to 12 months. Even today with the progress in the various therapeutic methods thereof, the 5-year survival from 1986 to 1990 is 8.0%, compared with the 5-year survival 20 years ago namely the 5-year survival from 1969 to 1975, which was 11.9%. Thus, almost no difference is observed (Neurology Progress, 43(3), 338-350, 1999). Accordingly, it is strongly desired that an effective therapeutic method thereof should be established.
Tumor cells of glioblastoma are the most undifferentiated among brain tumors, so the tumor cells have high potentials of migration and proliferation and are highly invasive, leading to very poor prognosis.
Glioblastoma is classified into primary glioblastoma de novo and secondary glioblastoma, depending on the difference in the gene mechanism of the malignant transformation of undifferentiated astrocyte or precursor cells. Secondary glioblastoma occurs in a young generation of 45 years old or younger. In 4 to 5 years on average, secondary glioblastoma occurs from astrocytoma through undifferentiated astrocytoma. Meanwhile, primary glioblastoma de novo frequently occurs in an older generation of the mean age of 55 years old. Generally, primary glioblastoma de novo takes the form of fulminant glioblastoma (referred to as de novo glioblastoma as well) which occurs within 3 months from the state with no clinical or pathological abnormalities [Pathology and Genetics of the Nervous Systems. 29-39 (IARC Press, Lyon, France, 2000)].
Glioblastoma migrates along myelinated nerve and spreads widely in the central nerve. Therefore, surgical treatment thereof cannot show any satisfactory therapeutic effect (Neurol. Med. Chir. (Tokyo) 34, 91-94, 1994; Neurol. Med. Chir. (Tokyo) 33, 425-458, 1993; Neuropathology 17, 186-188, 1997). Additionally, pharmaceutical agents with an indication for glioblastoma are limited in Japan to for example ranimustine and interferon. Additionally, the efficacy thereof is insufficient.
α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors belong to ionotropic glutamate receptors are responsible for rapid nerve conduction of almost all excitatory synapses (Trends Neurosci. 16, 359-365, 1993; Annu. Rev. Neurosci. 17, 31-108, 1994; Prog. Neurobiol. 54, 581-618, 1998). AMPA receptors are expressed in many glyacytes like those in neurons (Trends Pharmacol. Sci. 21, 252-258, 2000). AMPA receptors are composed of four subunits, namely GluR1 through GluR4. The Ca2+ permeability of an AMPA receptor depends on the composition with the subunits thereof. Specifically, an AMPA receptor with the GluR2 subunit has low Ca2+ permeability, while an AMPA receptor without GluR2 has high Ca2+ permeability. A higher content of the GluR2 subunit decreases the Ca2+ permeability more (Trends Neurosci. 16, 359-365, 1993; Annu. Rev. Neurosci. 17, 31-108, 1994; Prog. Neurobiol. 54, 581-618, 1998). Further, the unique feature of GluR2 is described as follows. In case that one amino acid residue in the second hydrophobic region (M2), which is originally arginine (R), is substituted with glutamine (Q), the resulting homomer receptor composed of the substituted GluR2(Q) has high Ca2+ permeability (Trends Neurosci. 16, 359-365, 1993, Annu. Rev. Neurosci. 17, 31-108, 1994). In other words, such receptor at a higher content of the GluR2 subunit when the subunit is GluR(Q) type is highly permeable to Ca2+. When the subunit is GluR2(R), however, the resulting receptor does not shows any Ca2+ permeability.
Concerning glioma cells and glutamate, reports showed that the expression of the GluR2 gene is low in C6-glioma (J. Neurosci. Res. 46, 164-178, 1996) and that 66% of glioblastoma culture cells respond to a glutamate receptor agonist and depolarize (Eur. J. Neurosci. 10, 2153-2162, 1998).
The following reports have been issued about the inhibiting action of antagonists against the ionotropic glutamate receptor family on glioma and the like.
1) Patent reference 1 discloses an invention relating to the method for inhibiting the interaction between AMPA receptor complexes and glutamate for cancer treatment, wherein specific examples of brain tumor include medulloblastoma classified as a fetal tumor and human brain astrocytoma as one glioma type. The Reference describes the in vitro effect of an antagonist GYK152446 against AMPA receptor on brain astrocytoma.
However, the reference does not disclose or suggests the use of the antagonist against AMPA receptor for treatment of glioblastoma with high malignancy to have resistance to radiotherapy or chemotherapy.
2) Non-patent reference 1 by the inventor described above includes a description that antagonists against NMDA- and AMPA receptors are highly sensitive to tumor cells derived from peripheral cells but poorly sensitive to tumor cells derived from nerve and glyacites. Additionally, the reference describes that these antagonists are useful as therapeutic agents of peripheral cancer. Thus, the effect of the invention on glioblastoma cannot be anticipated on the basis of the in vitro effect using the tumor cells with lower malignancy levels than that of glioblastoma.
3) Non-patent reference 2 reports that MK-801 and memantin as antagonists against NMDA receptor exert a proliferation inhibition in the C6 and RG2 glioma transplanted rat models.
However, it is criticized that the previous research on glioma using such animal models are criticized since they do not represent real growth of tumor (non-patent Reference 3).
4) Additionally, non-patent reference 4 as one critical review of the non-patent reference 1 suggests the possibility of the inhibition AMPA receptors and NMDA receptors as a multiple therapy for glioma. However, the authors are suspicious about whether or not the animal models using C6 and RG2 glioma used in the non-patent reference 1 can reflect human tumor.
Based on those described above, these previous techniques do not include any specific descriptions about the possibility that antagonists against AMPA receptor will become a therapeutic agent of the most malignant human glioblastoma among various types of glioma. The effect on C6 and RG2 glioma does not suggest any possible therapeutic effect on human glioblastoma.
Thus, the invention is not described in any these previous techniques, and it cannot be derived readily from them.
[Patent Reference 1]
PCT International Publication pamphlet WO 00/24395
[Non-Patent Reference 1]
Proceedings of the National Academy of Sciences of United States of America 98 (11), 6372-6377, 2001
[Non-Patent Reference 2]
Nature Medicine 7(9), 1010-1015, 2001
[Non-Patent Reference 3]
Nature Medicine 6(4), 369-370, 2000
[Non-Patent Reference 4]
Nature Medicine 7(9), 994-995, 2001